Continued smoking by head and neck cancer patients is associated with poor survival, a greater risk of disease recurrence and a second primary tumor, reduced treatment efficacy, and adverse treatment-related complications. Nevertheless, 25-35 percent of patients who smoked prior to the diagnosis continue to do so following treatment. To date, rigorous studies of smoking cessation interventions for cancer patients have yet to be conducted. Since the presence of significant depressive symptoms - which can impede successful quitting - are common among cancer patients, it may be particularly important to address negative affect within a cessation program for this population using an antidepressant (i.e., bupropion). However, in light of barriers to bupropion use, including cost and adverse side effects, discerning subgroups of smokers in need of intensive (i.e., use of pharmacologic treatments, in addition to counseling and nicotine replacement therapy [NRT]) vs. moderate (i.e., involving counseling and NRT alone) treatments has become a priority in the field of nicotine addiction research. The presence vs. the absence of significant depressive symptoms may be a useful way for matching smokers to optimal treatments (i.e., depressed smokers may require bupropion in addition to counseling and NRT, whereas non-depressed smokers may be able to achieve cessation with NRT and counseling alone). Further, the mechanism through which bupropion affects smoking behavior has yet to be clearly delineated, although it may be through bupropion's influence on affect. Thus, this placebo-controlled randomized trial with 366 head and neck cancer patients will: 1) Compare intensive smoking cessation treatment (i.e., bupropion, NRT, counseling) to moderate smoking cessation treatment (i.e., placebo, NRT, counseling) for increasing quit rates among head and neck cancer patients (Aim 1);2) Determine whether the presence of significant depressive symptoms moderate the effect of bupropion on quit rates (Aim 2); and 3) Explore whether the effect of bupropion on smoking cessation is mediated by changes in positive or negative affect (Aim 3). The primary outcome for this study will be continuous abstinence, assessed using the time-line follow-back method, from the quit day until the 2-, 6-, and 12-month follow-up assessments. Overall, data from this study may guide the use of bupropion for treating nicotine addiction among head and neck cancer patients. In particular, our results may provide a guide for matching intensive vs. moderate cessation interventions according to the psychological needs of the cancer patient. Further, understanding the role of changes in affect as the mechanism that underlies the effects of bupropion may help to refine mood management clinical approaches for cancer patients. In turn, our findings may help guide the implementation of smoking cessation treatments for all cancer patients within Comprehensive Cancer Centers in the US.